Central 5-HTergic hyperactivity induces myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)-like pathophysiology

  • J Transl Med. 2024 Jan 8;22(1):34. doi: 10.1186/s12967-023-04808-x.
Jin-Seok Lee  1  2 ,  Ji-Yun Kang  2 ,  Samuel-Young Park  3 ,  Seung-Ju Hwang  2 ,  Sung-Jin Bae  4 ,  Chang-Gue Son  5  6
Affiliations
  • 1. Research Center for CFS/ME, Daejeon Hospital of Daejeon University, Daejeon, Republic of Korea.
  • 2. Institute of Bioscience & Integrative Medicine, Daejeon University, Daejeon, Republic of Korea.
  • 3. Korean Medical College of Daejeon University, Daejeon, Republic of Korea.
  • 4. College of Medicine, Kosin University, Busan, Republic of Korea.
  • 5. Research Center for CFS/ME, Daejeon Hospital of Daejeon University, Daejeon, Republic of Korea. [email protected].
  • 6. Institute of Bioscience & Integrative Medicine, Daejeon University, Daejeon, Republic of Korea. [email protected].
PMID: 38191373 DOI: 10.1186/s12967-023-04808-x
Abstract

Objectives: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a significant medical challenge, with no indisputable pathophysiological mechanism identified to date.

Methods: Based on clinical clues, we hypothesized that 5-hydroxytryptamine (5-HT) hyperactivation is implicated in the pathogenic causes of ME/CFS and the associated symptoms. We experimentally evaluated this hypothesis in a series of mouse models.

Results: High-dose selective serotonin reuptake inhibitor (SSRI) treatment induced intra- and extracellular serotonin spillover in the dorsal raphe nuclei of mice. This condition resulted in severe fatigue (rota-rod, fatigue rotating wheel and home-cage activity tests) and ME/CFS-associated symptoms (nest building, plantar and open field test), along with dysfunction in the hypothalamic-pituitary-adrenal (HPA) axis response to exercise challenge. These ME/CFS-like features induced by excess serotonin were additionally verified using both a 5-HT synthesis inhibitor and viral vector for Htr1a (5-HT1A receptor) gene knockdown.

Conclusions: Our findings support the involvement of 5-HTergic hyperactivity in the pathophysiology of ME/CFS. This ME/CFS-mimicking animal model would be useful for understanding ME/CFS biology and its therapeutic approaches.

Keywords
5-HT1A receptor; Desensitization; Fatigue, serotonin; Hypocortisolism; Myalgic encephalomyelitis/chronic fatigue syndrome.
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